Faculty Bibliography

Asian women have lower rates of hip and forearm fractures despite lower areal BMD (aBMD) by DXA compared with white women and other racial groups. We hypothesized that the lower fracture rates may be explained by more favorable measurements of volumetric BMD (vBMD) and microarchitectural properties, despite lower areal BMD. To address this hypothesis, we used high-resolution pQCT (HRpQCT), a new method that can provide this information noninvasively. We studied 63 premenopausal Chinese-American (n = 31) and white (n = 32) women with DXA and HRpQCT. aBMD by DXA did not differ between groups for the lumbar spine (1.017 +/- 0.108 versus 1.028 +/- 0.152 g/cm(2); p = 0.7), total hip (0.910 +/- 0.093 versus 0.932 +/- 0.134 g/cm(2); p = 0.5), femoral neck (0.788 +/- 0.083 versus 0.809 +/- 0.129 g/cm(2); p = 0.4), or one-third radius (0.691 +/- 0.052 versus 0.708 +/- 0.047 g/cm(2); p = 0.2). HRpQCT at the radius indicated greater trabecular (168 +/- 41 versus 137 +/- 33 mg HA/cm(3); p = <0.01) and cortical (963 +/- 46 versus 915 +/- 42 mg HA/cm(3); p < 0.0001) density; trabecular bone to tissue volume (0.140 +/- 0.034 versus 0.114 +/- 0.028; p = <0.01); trabecular (0.075 +/- 0.013 versus 0.062 +/- 0.009 mm; p < 0.0001) and cortical thickness (0.98 +/- 0.16 versus 0.80 +/- 0.14 mm; p < 0.0001); and lower total bone area (197 +/- 34 versus 232 +/- 33 mm(2); p = <0.001) in the Chinese versus white women and no difference in trabecular number, spacing, or inhomogeneity before adjustment for covariates. Similar results were observed at the weight-bearing tibia. At the radius, adjustment for covariates did not change the direction or significance of differences except for bone, which became similar between the groups. However, at the tibia, adjustment for covariates attenuated differences in cortical BMD and bone area and accentuated differences in trabecular microarchitecture such that Chinese women additionally had higher trabecular number and lower trabecular spacing, as well as inhomogeneity after adjustment. Using the high-resolution technology, the results provide a mechanistic explanation for why Chinese women have fewer hip and forearm fractures than white women.

BACKGROUND:Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis. METHODS AND RESULTS/RESULTS:CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: -77.8% to -9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: -20.1% to -8.1%) in CIMT. CONCLUSIONS:Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.

OBJECTIVES/OBJECTIVE:We sought to quantify the mortality rates associated with absent and low positive (CAC 1 to 10) coronary artery calcium (CAC). BACKGROUND:There is increasing interest in the absence of CAC as a "negative" cardiovascular risk factor. However, published event rates for individuals with no CAC vary, likely owing to differences in baseline risk, follow-up period, and outcome ascertainment. The prognostic significance of low CAC (CAC 1 to 10) is not well described. METHODS:Annualized all-cause mortality rates were assessed in 44,052 consecutive asymptomatic patients referred for CAC testing. Mean follow-up of the cohort was 5.6 +/- 2.6 years (range 1 to 13 years). RESULTS:A total of 19,898 patients (45%) had no CAC on screening electron beam tomography, whereas 5,388 (12%) had low levels of CAC (CAC 1 to 10), and 18,766 (43%) had CAC >10. There were 104 deaths in those with no CAC (0.52%), 58 deaths in those with CAC 1 to 10 (1.06%), and 739 deaths in those with CAC >10 (3.96%). Annualized all-cause mortality rates for CAC = 0, CAC 1 to 10, and CAC >10 were 0.87, 1.92, and 7.48 deaths/1,000 person-years, respectively. The hazard ratio (HR) for all-cause mortality among CAC 1 to 10 versus CAC = 0 after adjustment for traditional risk factors was 1.99 (95% confidence interval [CI]: 1.44 to 2.75). Smoking (HR: 3.97, 95% CI: 2.75 to 5.41) and diabetes mellitus (HR: 3.36, 95% CI: 2.09 to 5.41) were associated with few events observed in CAC = 0 group. CONCLUSIONS:In appropriately selected asymptomatic patients, the absence of CAC predicts excellent survival with 10-year event rates of approximately 1%. A finding of 0 CAC might be used as a rationale to emphasize lifestyle therapies rather than pharmacotherapy and to forgo repeated imaging studies. Individuals with low CAC score (CAC 1 to 10) are at increased risk above individuals with a 0 score and could be considered a distinct risk group by physicians and investigators.

The Agatston total coronary artery calcium (CAC) score, derived from a non-contrast CT scan of the heart (also known as the "heartscan") in asymptomatic and symptomatic patients, has been shown to provide incremental and independent assessment to conventional risk factors based upon literally hundreds of studies published from around the world. However, recent data have emerged to indicate that there is additional information which can be derived from a "heartscan" beyond the calcium score. These include recent data on the applicability across ethnic sub-groups, prognostication in the elderly, defining "heart age" versus chronological age for individual risk stratification, evaluating CAC distribution in addition to total CAC score, and looking beyond the coronary arteries regarding left ventricular size, aortic root/thoracic aorta diameter, and epicardial fat.

BACKGROUND:Aspergillus fumigatus is a common airborne fungal pathogen for humans. It frequently causes an invasive aspergillosis (IA) in immunocompromised patients with poor prognosis. Potent antifungal drugs are very expensive and cause serious adverse effects. Their correct application requires an early and specific diagnosis of IA, which is still not properly achievable. This work aims to a specific detection of A. fumigatus by immunofluorescence and the generation of recombinant antibodies for the detection of A. fumigatus by ELISA. RESULTS:The A. fumigatus antigen Crf2 was isolated from a human patient with proven IA. It is a novel variant of a group of surface proteins (Crf1, Asp f9, Asp f16) which belong to the glycosylhydrolase family. Single chain fragment variables (scFvs) were obtained by phage display from a human naive antibody gene library and an immune antibody gene library generated from a macaque immunized with recombinant Crf2. Two different selection strategies were performed and shown to influence the selection of scFvs recognizing the Crf2 antigen in its native conformation. Using these antibodies, Crf2 was localized in growing hyphae of A. fumigatus but not in spores. In addition, the antibodies allowed differentiation between A. fumigatus and related Aspergillus species or Candida albicans by immunofluorescence microscopy. The scFv antibody clones were further characterized for their affinity, the nature of their epitope, their serum stability and their detection limit of Crf2 in human serum. CONCLUSION/CONCLUSIONS:Crf2 and the corresponding recombinant antibodies offer a novel approach for the early diagnostics of IA caused by A. fumigatus.

BACKGROUND:This study is a comparative epigenetic evaluation of the methylation status of the DLC1 tumor suppressor gene in naturally-occurring canine lymphoma. Canine non-Hodgkin's lymphoma (NHL) has been proposed to be a relevant preclinical model that occurs spontaneously and may share causative factors with human NHL due to a shared home environment. The canine DLC1 mRNA sequence was derived from normal tissue. Using lymphoid samples from 21 dogs with NHL and 7 normal dogs, the methylation status of the promoter CpG island of the gene was defined for each sample using combined bisulfite restriction analysis (COBRA), methylation-specific PCR (MSP), and bisulfite sequencing methods. Relative gene expression was determined using real-time PCR. RESULTS:The mRNA sequence of canine DLC1 is highly similar to the human orthologue and contains all protein functional groups, with 97% or greater similarity in functional regions. Hypermethylation of the 5' and 3' flanking regions of the promoter was statistically significantly associated with the NHL phenotype, but was not associated with silencing of expression or differences in survival. CONCLUSION/CONCLUSIONS:The canine DLC1 is constructed highly similarly to the human gene, which has been shown to be an important tumor suppressor in many forms of cancer. As in human NHL, the promoter CpG island of DLC1 in canine NHL samples is abnormally hypermethylated, relative to normal lymphoid tissue. This study confirms that hypermethylation occurs in canine cancers, further supporting the use of companion dogs as comparative models of disease for evaluation of carcinogenesis, biomarker diagnosis, and therapy.